Pediatric considerations for proton therapy

Introduction

Approximately 10,500 cases of childhood cancer are diagnosed each year, which represent about 1% of all new cancers in the United States. Nearly 45% of these cancers will either be acute lymphoblastic leukemia or brain and other central nervous system (CNS) tumors. More than 80% of patients afflicted with childhood cancer will be alive at 5 years from initial diagnosis. In 2014, an estimated 1350 deaths occurred secondary to cancer in children 14 years of age or younger. About 25% of deaths in children who survive at least 5 years from their diagnosis die of treatment-related complications. Many of the late effects of treatment can be linked to the use of radiotherapy (RT). The reduction of RT dose has been implicated in the corresponding reduction in late toxicities, including secondary neoplasms.

Proton therapy has the potential to reduce complications in children because of the reduction of integral dose to normal tissues when compared with photons. The ability of protons to spare normal tissues beyond a specified depth can be advantageous to the somatic and function of the organ or tissue beyond the target and may result in the reduction of secondary neoplasms.

Unique problems in children

The late effects of RT in children can be different from those in adults. Although the predominant manifestation of radiation injury in the adult will usually be fibrogenic or inflammatory, which contributes to loss of organ function, in children, there is an added clinical manifestation of growth delay and impaired maturation of the organ. Young children under 7 years of age are particularly vulnerable if the brain and musculoskeletal organs are irradiated because this is the time when these organ systems are growing and developing. Teenagers are particularly vulnerable to secondary neoplasms when the breast tissue is irradiated during puberty, resulting in a higher incidence of secondary breast cancer compared with irradiation of a young child or adult. Hence, strategies to eliminate or reduce RT during these vulnerable periods have been used. For children under 3 years of age with brain tumors, adjuvant chemotherapy has been used to delay the start of RT until the child is 3 years old. In ependymoma, for example, only 40% and 20% of children are progression-free at 2 years and 5 years, respectively, with this approach. ^, This dogma has been challenged by researchers from St. Jude Children’s Research Hospital, who have shown a 3-year progression-free survival (PFS) rate of 74.7% in 88 children with a median age of 2.9 years; neurocognitive testing showed stable cognitive findings, with more than half of the children tested at 2 years after RT. Currently, many young children with brain tumors to be treated with RT are referred for proton therapy to minimize late effects.

Proton therapy literature on children

Although the theoretical benefit of proton therapy is obvious, many in the pediatric oncology community have questioned whether protons have the same tumor control efficacy as photons. Others have questioned whether the reduction of integral dose will have a clinically significant effect on long-term toxicity when compared with very sophisticated photon plans possible using intensity-modulated radiation therapy (IMRT), volumetric arc therapy, and tomotherapy. Although few publications deal with protons and their effectiveness for tumor control, the current literature suggests that protons are equivalent to photons with regard to local control of tumors. Furthermore, literature is evolving to suggest that some acute and late effects can be minimized by using proton therapy.

Medulloblastoma

Patients with medulloblastoma have a lot to gain by not receiving radiation doses to organs anterior to the spine during the craniospinal portion of the treatment. Structures such as the thyroid gland and breast tissue are particularly prone to developing secondary cancers. Cardiovascular late effects after RT have also been reported for patients with medulloblastoma. Craniospinal doses for patients with average-risk and standard-risk disease are 23.4 and 36 Gy. The tumor bed is given an additional RT boost dose to a total dose of 54 to 55.8 Gy.

In a multiinstitution study of 88 patients with standard-risk medulloblastoma given chemotherapy and proton ( n = 45) or photon ( n = 43) therapy, the 6-year relapse-free survival rates were 78.8% and 76.5%, repectively, whereas the 6-year overall survival (OS) rates were 82.0% and 87.6% for protons and photons, respectively. Patterns of failure were similar among both groups. At MD Anderson, the 3-year event-free survival (EFS) rates were 77.0% and 53.0%, whereas the 3-year OS rates were 90.7% and 73.4% for standard ( n = 63) and high-risk ( n = 33) groups, respectively, which was similar to the historical photon literature.

A comparison of adult medulloblastoma patients treated with protons ( n = 19) or photons ( n = 21) revealed that the proportions of patients with more than 5% body weight loss ( P = .004), grade 2 nausea and vomiting ( P = .004), medical management of esophagitis ( P < .001), reduction of white count ( P = .04), reduction of hemoglobin ( P = .009), and reduction of platelets ( P = .05) were smaller with protons compared with photons.

A recent phase II trial of 59 patients treated with proton therapy for medulloblastoma revealed that the cumulative incidence of Pediatric Oncology Group (POG) grade 3 to 4 ototoxicity was 16% at 5 years. The full-scale intelligence quotient decreased by 1.5 points per year without a change in perceptual reasoning index and working memory. The cumulative index of any neuroendocrine deficit at 5 years was 55%. A recent comparison of grade 3 to 4 ototoxicity that used three different ototoxicity scales (POG, Brock, and International Society of Pediatric Oncology [SIOP – Boston]) showed essentially the same proportions of proton and photon patients developing hearing loss. Although protons led to a reduction in the RT dose to the cochlea relative to photons, this did not translate into hearing preservation, probably because patients also received cisplatin.

Hypothyroidism has also been shown to be less common among children receiving proton craniospinal irradiation (CSI). A retrospective comparison of standard-risk medulloblastoma patients treated with protons versus photons showed that the hypothyroidism rate was reduced from 69% to 23% with protons ( P < .001). Use of photons for CSI was also associated with a greater risk of sex hormone deficiency (19%–3%; P = .025), a requirement for any endocrine replacement therapy (78%–55%; P = .030), and a greater height standard deviation score difference compared with proton CSI. No differences were found in the incidence of growth hormone deficiency, adrenal insufficiency, or precocious puberty.

Ependymoma

As mentioned, RT is now routinely used to treat young children with ependymoma. Children who are at least 1 year old receive adjuvant RT to the tumor bed. The only exception for postoperative RT is for a child with a grade II supratentorial tumor that has undergone gross total resection. Investigators from Boston have reported comparable local control and PFS with protons compared with other photon series. The 3-year PFS rates were 88% and 54% for gross total and subtotally resected disease from using protons, respectively, and compares well with the St. Jude 5-year PFS rates of 91.5% and 41% for gross total and subtotally resected disease in children, respectively. At the Texas Children’s Hospital and the MD Anderson Proton Center, investigators compared the 3-year PFS rates for children with ependymoma treated with both RT modalities. The 3-year PFS rates were 82% and 60% for proton and photon patients, respectively ( P = .031); however, gross total resection was more common in the proton group than in the photon group (93% vs. 76%, respectively; P = .043).

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